SPID#: 22 Unlike typical simian immunodeficiency virus infection of macaques,which induces an AIDS-like syndrome, SIVsmmPBj infection in pig-tailed macaques induces an acutely lethal disease. Our group has been involved in elucidating the genetic and biologic mechanisms involved in the induction of this unusual disease. Previous work has shown that multiple viral determinants contribute to the pathogenesis of disease. To further investigate the genetic elements that may contribute to acute disease, we have constructed a molecular clone of SIVsmmPBj which lacks a functional nef gene. Analysis of this virus in vitro shows that it does not appear to have the same biologic activity as typical SIVsmmPBj, i.e. no replication in unstimulated cells, and no induction of PBMC proliferation. When inoculated into pig-tailed macaques, this virus (termed SIVsmmPBjDnef) did not induce any acute disease. Since the time of infection, animals have remained healthy, with no signs of disease. Recently, we have started to examine the biologic characteristics of disease. Two of the unique features of this disease are the acute lymphopenia, which appears by day 3 post infection, and the lymphoid hyperplasia observed in the intestinal tract. Investigations into this phenomenon have shown that the lymphopenia is most likely due to the induction of gut-specific integrins on cells infected with SIVsmmPBj, thus redirecting the cells to the intestinal area. Another characteristic of this virus is the acute pathology which develops in the gut. Others have shown that there is an increase in the levels of IL-6 and TNFa after SIVsmmPBj infection. In conjunction with this we have started to examined what role apoptosis plays in pathogenesis. High levels of apoptotic cells are present in intestinal tissue obtained from SIVsmmPBj-infected animals. Cells undergoing apoptosis appear to be uninfected, thus confirming reports of others investigating typical HIV and SIV infection.